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- PDB-6pf3: Crystal structure of human thymidylate synthase Delta (7-29) in c... -

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Basic information

Entry
Database: PDB / ID: 6pf3
TitleCrystal structure of human thymidylate synthase Delta (7-29) in complex with dUMP and 2-(4-((2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl)benzamido)-4-chlorobenzoic acid
ComponentsThymidylate synthase
Keywordstransferase/transferase inhibitor / Inhibitor / TS / TRANSFERASE / transferase-transferase inhibitor complex
Function / homology
Function and homology information


uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion ...uracil metabolic process / response to organophosphorus / intestinal epithelial cell maturation / response to folic acid / Interconversion of nucleotide di- and triphosphates / response to vitamin A / thymidylate synthase / sequence-specific mRNA binding / cartilage development / tetrahydrofolate interconversion / thymidylate synthase activity / folic acid binding / dTMP biosynthetic process / dTTP biosynthetic process / G1/S-Specific Transcription / DNA biosynthetic process / developmental growth / response to glucocorticoid / mRNA regulatory element binding translation repressor activity / response to progesterone / response to cytokine / liver regeneration / response to toxic substance / circadian rhythm / methylation / response to ethanol / mitochondrial inner membrane / negative regulation of translation / mitochondrial matrix / response to xenobiotic stimulus / protein homodimerization activity / mitochondrion / nucleus / cytosol / cytoplasm
Similarity search - Function
Thymidylate Synthase; Chain A / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase / Thymidylate synthase, active site / Thymidylate synthase active site. / Thymidylate synthase / Thymidylate synthase/dCMP hydroxymethylase domain / Thymidylate synthase/dCMP hydroxymethylase superfamily / Thymidylate synthase / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-OE7 / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / Thymidylate synthase
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.391 Å
AuthorsCzyzyk, D.J. / Valhondo, M. / Jorgensen, W.L. / Anderson, K.S.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)AI083146 United States
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)5T32AI007404 United States
CitationJournal: Eur.J.Med.Chem. / Year: 2019
Title: Structure activity relationship towards design of cryptosporidium specific thymidylate synthase inhibitors.
Authors: Czyzyk, D.J. / Valhondo, M. / Deiana, L. / Tirado-Rives, J. / Jorgensen, W.L. / Anderson, K.S.
History
DepositionJun 21, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 2, 2019Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2019Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thymidylate synthase
B: Thymidylate synthase
C: Thymidylate synthase
D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)135,74012
Polymers132,7564
Non-polymers2,9848
Water75742
1
A: Thymidylate synthase
C: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8706
Polymers66,3782
Non-polymers1,4924
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5510 Å2
ΔGint-28 kcal/mol
Surface area20710 Å2
MethodPISA
2
B: Thymidylate synthase
hetero molecules

B: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8706
Polymers66,3782
Non-polymers1,4924
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_655-x+1,y,-z1
Buried area5470 Å2
ΔGint-27 kcal/mol
Surface area20410 Å2
MethodPISA
3
D: Thymidylate synthase
hetero molecules

D: Thymidylate synthase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,8706
Polymers66,3782
Non-polymers1,4924
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_656-x+1,y,-z+11
Buried area5580 Å2
ΔGint-29 kcal/mol
Surface area20510 Å2
MethodPISA
Unit cell
Length a, b, c (Å)89.144, 89.322, 163.480
Angle α, β, γ (deg.)90.00, 90.01, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein
Thymidylate synthase / / TSase


Mass: 33189.070 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: TYMS, TS, OK/SW-cl.29 / Production host: Escherichia coli BL21(DE3) (bacteria) / Strain (production host): BL21(DE3) / Variant (production host): TX-61 / References: UniProt: P04818, thymidylate synthase
#2: Chemical
ChemComp-UMP / 2'-DEOXYURIDINE 5'-MONOPHOSPHATE / DUMP / Deoxyuridine monophosphate


Mass: 308.182 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C9H13N2O8P
#3: Chemical
ChemComp-OE7 / 2-({4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]benzene-1-carbonyl}amino)-4-chlorobenzoic acid


Mass: 437.836 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C21H16ClN5O4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 42 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.49 Å3/Da / Density % sol: 50.7 %
Crystal growTemperature: 295.15 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: Well solution 18 % PEG monomethyl ether 5000, 0.1 M Bis-Tris Drop ratio 1:1 enzyme mix/well solution

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 24-ID-E / Wavelength: 0.97915 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.39→50 Å / Num. obs: 50336 / % possible obs: 98.9 % / Redundancy: 3.7 % / CC1/2: 0.998 / Rsym value: 0.072 / Net I/σ(I): 12.95
Reflection shellResolution: 2.39→2.54 Å / Redundancy: 3.6 % / Mean I/σ(I) obs: 1.46 / Num. unique obs: 7813 / CC1/2: 0.828 / Rsym value: 0.941 / % possible all: 95.5

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Processing

Software
NameVersionClassification
PHENIX(1.15.2_3472: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1HZW

1hzw


Resolution: 2.391→44.661 Å / SU ML: 0.44 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 37.8 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2888 1988 3.97 %
Rwork0.257 --
obs0.2583 50053 98.4 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.391→44.661 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8834 0 204 42 9080
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029280
X-RAY DIFFRACTIONf_angle_d0.48712639
X-RAY DIFFRACTIONf_dihedral_angle_d9.2865359
X-RAY DIFFRACTIONf_chiral_restr0.041355
X-RAY DIFFRACTIONf_plane_restr0.0031630
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3913-2.45110.43071370.44423109X-RAY DIFFRACTION89
2.4511-2.51740.43531390.40563430X-RAY DIFFRACTION99
2.5174-2.59150.45271400.38123361X-RAY DIFFRACTION98
2.5915-2.67510.4331320.35823440X-RAY DIFFRACTION99
2.6751-2.77070.41821430.3523487X-RAY DIFFRACTION99
2.7707-2.88160.39251420.31883464X-RAY DIFFRACTION99
2.8816-3.01280.32161390.32013437X-RAY DIFFRACTION100
3.0128-3.17160.35391450.31743458X-RAY DIFFRACTION99
3.1716-3.37020.25651430.30813438X-RAY DIFFRACTION99
3.3702-3.63030.3421530.28073449X-RAY DIFFRACTION99
3.6303-3.99540.33421360.25823502X-RAY DIFFRACTION100
3.9954-4.57310.23491490.20553460X-RAY DIFFRACTION99
4.5731-5.75970.22681460.20363493X-RAY DIFFRACTION99
5.7597-44.66880.20091440.1843537X-RAY DIFFRACTION98

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